ORIGINAL PAPER
`
`HE‘) THE INTERNATIONALJOURNAL OF
`
`CLINICAL PRACTICE
`
`Efficacy and safety of fesoterodine 8 mg in subjects with
`overactive bladder after a suboptimal response to
`tolterodine ER
`
`S. A. Kaplan,‘ L. Cardozo} S. Herschorn,3 L. Grenabo,4 M. Carlsson,5 D. Arumi,6 T. J. Crook,7
`L. Whe|an,7 D. Scho|fie|d,7 F. Ntanios,5 on behalf of the Assessment of Fesoterodine after Tolterodine
`ER (AFTER) Study Group
`
`SUMMARY
`
`Aims: To assess fesoterodine 8 mg efficacy over time and vs. placebo in subjects
`with
`overactive bladder
`(OAB) who responded suboptimally to tolterodine
`extended release (ER) 4 mg. Methods: In a 12-week, double-blind trial, subjects
`with self-reported OAB symptoms for 2 6 months, mean of 2 8 micturitions and
`2 2 to <15 urgency urinary incontinence (UUI) episodesr'24 h, and suboptimal
`response to tolterodine ER 4 mg (defined as 3 50% reduction in UUI episodes
`during 2-week run-in) were randomised to fesoterodine (4 mg for
`1 week, 8 mg
`for 11 weeks) or placebo once daily. Change from baseline to week 12 in UUI
`episodes (primary end—point) was analysed in step—wise fashion: first, baseline vs.
`week 12 for fesoterodine;
`if significant,
`then change from baseline to week 12
`for
`fesoterodine
`vs.
`placebo. Results:
`By week
`12,
`subjects
`receiving
`fesoterodine Smg had significantly greater
`improvement
`from baseline
`vs.
`placebo in UUI episodes, urgency episodes and scores on the Patient Perception
`of Bladder Control, Urgency Perception Scale and OAB Questionnaire Symptom
`Bother and Hea|th—Re|ated Quality of Life scales and domains (all p< 0.05).
`50% and 70% UUI responder rates were also significantly higher with fesotero-
`dine 8 mg vs. placebo at week 12 (p < 0.05). Dry mouth (placebo, 4%, 121301;
`fesoterodine,
`16.6%,
`511308)
`and
`constipation
`(placebo,
`1.3%,
`41301;
`fesoterodine,
`3.9%,
`121308) were
`the most
`frequent
`adverse
`events.
`Conclusions: Subjects who responded suboptimally to tolterodine ER 4 mg
`showed
`significant
`improvements
`in UUI
`and other DAB symptoms
`and
`patient—reported
`outcomes, with
`good
`tolerability,
`during
`treatment with
`fesoterodine 8 mg vs. placebo.
`
`What's known
`Some patients with overactive bladder who
`experience suboptimal treatment outcomes with one
`antimuscarinic may benefit from treatment with a
`different agent, Two prospectively—designed, placebo-
`controlled, head-to-head studies demonstrated that
`fesoterodine 8 mg is significantly more efficacious
`than tolterodine extended release 4 mg for improving
`UUI episodes and other bladder diary endpoints as
`well as patient-reported measures of symptom bother
`and health—related quality of life.
`
`What's new
`Subjects who responded suboptimally to tolterodine
`extended release 4 mg showed significantly greater
`improvements in urgency urinary incontinence
`episodes and other overactive bladder symptoms and
`patient-reported outcomes after treatment with
`fesoterodine 8 mg versus placebo. These data
`provide further evidence suggesting that some
`patients with overactive bladder including urgency
`urinary incontinence may experience additional
`treatment benefit with fesoterodine 3 mg versus
`tolterodine ER 4 mg.
`
`Introduction
`
`Urgency urinary incontinence (UUI) is highly both-
`ersome and negatively impacts health-related quality
`of life (HRQL) (1). UUI is associated with numerous
`comorbidities, such as falls and fractures,
`infections
`
`and depression (2), and a large proportion of the
`cost associated with overactive bladder
`(OAB)
`is
`attributable to UUI (3).
`Antimuscarinics are the first-line pharmacologic
`treatment for UUI and OAB. Some antimuscarinics,
`such as
`fesoterodine, are available in two doses,
`
`allowing the physician to individually titrate dosage
`for optimal efficacy and manageable side effects (4).
`Alternatively, some patients with OAB not achieving
`
`treatment outcomes with one agent may
`optimal
`benefit from treatment with a different antimuscari-
`
`nic (5-7). Two prospectively designed, placebo-con-
`trolled, head-to-head studies
`that
`compared the
`highest approved doses of fesoterodine (8 mg) and
`tolterodine extended release (ER)
`(4 mg) demon-
`strated that fesoterodine 8 mg was significantly more
`efficacious than tolterodine ER 4 mg in reducing
`UUI
`episodes and produced significantly higher
`diary-dry rates
`(8,9). Patient-reported outcomes
`measuring symptom bother and HRQL were also sig-
`nificantly improved following treatment with fesoter-
`odine 8 mg vs.
`tolterodine ER 4 mg (8,9). These
`findings are consistent with a post hoc analysis of an
`earlier trial, which showed that
`fesoterodine 8 mg
`
`© 2014 The Authors International Journal of Clinical Practice Published by John Wiley 8: Sons Ltd
`r'nt.l' Clin Pract, September 2014, 68, 9, 1065-1073. doi: 10.1111lijcp.124l-34
`This is an open access article under the terms of the Creative Commons Attribution—NonCommercial—NoDerivs License, which permits use and
`distribution in any medium, provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made.
`
`‘Weill Cornell Medical College,
`Cornell University, New York,
`NY, USA
`2King's College Hospital,
`London, UK
`3Sunnybrook Health Sciences
`Center, University of Toronto,
`Toronto, ON, Canada
`“Department of Urology,
`Sahlgrenska University Hospital,
`Goteborg, Sweden
`‘Pfizer Inc, New York, NY, usa
`‘Pfizer EU Medical Department,
`Madrid, Spain
`7Pfizer Ltd., Walton Oaks, UK
`
`Correspondence to:
`Steven A. Kaplan, MD,
`Weill Cornell Medical College,
`Department of Urology
`1300 York Avenue,
`New York, NY 10021, USA
`Tel.: + 212 756 4811
`Fax: + 212 T46 5329
`Email: kap|ans@med.corne|l.edu
`
`ClinicalTria|s.Gov ID:
`NCT01302054.
`
`Disclosures
`SAK has been a consultant and
`investigator for Pfizer Inc and
`has received speaker
`honorarium from Merck. LC has
`been a consultantfadvisor for
`Allergan, Astellas, Ethicon,
`Merck, Pfizer and Teva; a
`speaker for Astellas. and an
`investigator for Pfizer Inc. and
`Astellas. SH has been a
`consultant for Pfizer Inc,
`Astellas, Allergan. Merus and
`Eli Lilly," has received speaker
`honorarium from Pfizer Inc,
`Astellas. and Allergan; has
`been an investigator for Pfizer
`lnc., Astellas, and Allergan; and
`has received research funding
`from Allergan. LG has no
`financial relationships or
`commercial affiliations to
`disclose. MC and EN are
`employees of Pfizer Inc; DA is
`
`1065
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2090 - 0001
`
`

`
`1066
`
`Fesoterodine efficacy after suboptimal tolterodine response
`
`an employee of Pfizer EU; and
`TC, UN and D5 are employees
`of Pfizer Ltd.
`
`produced significantly greater improvements in UUI
`episodes, number of continent days/week, and other
`diary variables than tolterodine ER 4 mg (10).
`The objectives of this study were to assess the effi-
`cacy and safety of fesoterodine 3 mg in OAB patients
`who responded suboptimally to tolterodine ER 4 mg
`in a prospective, randomised, controlled trial.
`
`Materials and Methods
`
`Subjects
`This was a 12-week, randomised, double-blind, pla-
`cebo-controlled, parallel-group, multicentre
`study
`conducted at 156 sites in 15 countries in Europe,
`North America, Asia, and Africa between May 2011
`and May 2012 (ClinicalTrials.Gov ID: NCT01302054).
`Before subjects were randomised to the treatment
`study period, they entered a 2-week, open—label, run-
`in period to identify subjects who responded subop-
`timally to tolterodine ER 4 mg once daily (11). Sub-
`jects reporting a S 50% reduction in mean UUI
`episodes/24 h from the eligibility diary (week — 2)
`to the baseline diary (week 0) were randomised 1:1
`via a centralised system to 12 weeks of treatment
`with fesoterodine or placebo. Subjects randomised to
`fesoterodine received fesoterodine 4 mg once daily
`for the first week, followed by fesoterodine 8 mg for
`11 weeks. Study drug was to be taken once daily in
`the morning. The study was conducted in accordance
`with the Declaration of Helsinki,
`the International
`Conference on Harmonisation Good Clinical Practice
`
`regulatory requirements.
`local
`Guidelines, and all
`The appropriate Institutional Review Boards and
`Ethics Committees approved the protocol.
`Inclusion criteria were: men or women aged
`3 18 years,
`self-reported
`OAB
`symptoms
`for
`2 6 months, and at least ‘some moderate problems’
`reported on the Patient Perception of Bladder Con-
`dition (PPBC) (12) at screening visit; a mean of 2 2
`to < 15 mean UUI episodes (Urinary Sensation Scale
`rating of 5) and 2 8 micturitions per 24 h on a 3-
`day bladder diary at the eligibility visit (week — 2;
`beginning of the tolterodine ER run-in); and S 50%
`change in mean UUI episodes/24 h between eligibil-
`ity and randomisation (baseline) visits (week 0; end
`of the tolterodine ER run-in).
`
`Exclusion criteria included any condition contrain-
`dicating use of tolterodine or fesoterodine or condi-
`tions that may affect assessment of bladder function,
`such as neurological conditions suspected of influ-
`encing bladder function, predominant stress urinary
`incontinence, lower urinary tractfpelvic surgery with
`ongoing effect on bladder function, pelvic organ pro-
`lapse, clinically significant bladder outflow obstruc-
`tion evidenced by previous history of acute urinary
`
`retention requiring catheterisation, or postvoid resid-
`ual volume > 200 ml. Subjects with clinically signifi-
`cant or recurrent urinary tract
`infection;
`treatment
`with 2 3 antimuscarinic OAB medications within
`
`12 months before screening; new or unstable use of
`diuretics, or-blockers, 5—alpha reductase inhibitors,
`estrogens, or tricyclic antidepressants; treatment with
`drugs capable of influencing hepatic metabolism with
`potential for drug-drug interaction; and initiation of
`electrostimulation or behavioural
`intervention pro-
`gramme within 4 weeks of screening.
`
`Efficacy outcomes
`The primary efficacy end-point was the change from
`baseline (after the tolterodine ER 4 mg run-in) to
`week 12 in the number of UUI episodes/24 h. The
`reduction from baseline to week 12 in UUI episodes
`for fesoterodine 8 mg was assessed. If significant, the
`change from baseline in number of UUI episodes.’
`24 h at week 12 for fesoterodine 8 mg was then
`compared with placebo.
`Secondary efficacy end—points included treatment
`differences in changes from baseline to week 4 in
`number of UUI episodes.’24 h; changes from baseline
`to weeks 4 and 12 in number of micturitions and
`
`(2 50% or
`rates
`responder
`urgency episodes/24 h;
`2 70% reductions in UUI episode frequency) from
`eligibility (prior to the run-in) and from baseline at
`weeks 4 and 12; diary-dry rate at weeks 4 and 12
`(percentage of subjects with > lUU1 episode on
`baseline diary and 0 UUI episodes on postbaseline
`diary); and changes from baseline to week 12 in
`PPBC (12), Urgency Perception Scale (UPS)
`(13),
`and Overactive Bladder Questionnaire (OAB—q) (14)
`scores.
`
`Statistical analysis
`The run-in period duration was based on previous
`data showing an approximately 70% reduction in
`UUI episodes during the first 2 weeks of antimuscar-
`inic treatment
`(15,16). The threshold of S 50%
`reduction in UUI episodes
`to define suboptimal
`response was based on comparison of cumulative
`distribution functions between active treatment and
`
`placebo groups from previous trials across all levels
`of percentage changes in UUI (l7,18); maximal sepa-
`ration was observed at approximately 50% change in
`UUI episodes. This is consistent with previous evi-
`dence-based recommendations for measuring treat-
`ment response in OAB subjects with UUI (1 1).
`Efficacy analyses were based on the full analysis set
`(all randomised subjects who took 3 1 close of study
`drug and had a baseline or postbaseline efficacy
`assessment). The safety analysis set included all sub-
`jects who were randomised and received 2 1 dose of
`
`© 2014 The Authors International Journal oi‘ Clinical Practice Published by John Wiley & Sons Ltd
`Int} Cfin Pratt, September 2014, 68, 9, 1065-1073
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2090 - 0002
`
`

`
`Fesoterodine efficacy after suboptimal tolterodine response
`
`1067
`
`double-blind study medication and/or took toltero-
`dine ER in the run-in period. Missing data were
`imputed with the last observation carried forward
`method.
`
`end-point, multiple
`the primary efficacy
`For
`hypothesis testing was conducted in a hierarchical
`sequentially rejective manner. The reduction from
`baseline to week 12 in UUI episodes for fesoterodine
`8 mg (within-group mean change) was
`assessed
`using a 1-sided t test based on an or-level of 2.5%. If
`significant, a l-sided test of the superiority of fesoter-
`odine 8 mg vs. placebo in reducing the mean num-
`ber of UUI episodes/24 h was conducted using an
`analysis of covariance model with treatment and
`country as factors and centred baseline value as a co-
`variate, based on an oi-level of 2.5%.
`Changes in secondary bladder diary variables and
`OAB—q scores were analysed using the same analysis
`of covariance model. Responder rates, 3-day diary-
`dry rates, and categorical changes in PPBC and UPS
`scores were analysed using the Cochran—Mantel—
`
`tests with modified ridit scoring stratified
`Haenszel
`by country. All tests of secondary outcomes were 2-
`sided based on an ot—level of 5%. All analyses were
`performed using Statistical Analysis Software versions
`8 and 9 (SAS Institute lnc., Cary, NC).
`Safety data, from both the tolterodine ER run-in
`phase and the double-blind phase. were summarised
`by treatment group.
`
`Results
`
`Subject disposition is presented in Figure 1. Demo-
`graphical and clinical characteristics were similar for
`the placebo and fesoterodine groups (Table 1). Sub-
`jects in both treatment groups had approximately
`4 UUI episocles."24 h at baseline.
`For the prirnary end—point, UUI episodes were sig-
`nificantly reduced from baseline to week 12 within each
`treatment group (p < 0.0001), and the mean reduction
`from baseline to week 12 in UUI episodes/24 h was
`significantly greater with
`fesoterodine
`8 mg vs.
`
`Screened
`in = 221 T]
`
`
`
`Assigned and treated with
`open-label tolterodine ER
`in = 990)
`
`Randomized to Placebo
`in = 320)
`
`Randomized I0 Fesoterodine
`in = 322)
`
`
`
`
`
`
`
`Safety population
`in = 301)
`
`FAS population
`(rt = 301)
`
`Discontinued in I 46; 15%)
`AEs(n = 10)
`Insufficient clinical
`response mid)
`Consent withdrawn (:1 = 14)
`Othertni 18)
`
`Completed
`in = 255; 85%)
`
`
`
`Safety population
`in = 308)
`
`
`
`
`
`FAS population
`(n = 308)
`
`
`
`Completed
`in = 281: 91%)
`
`Discontinued (n I 27; 9%)
`AEs(n=1tl)
`Insufficient clinical
`response ml 2)
`Consent withdrawn (n = 6)
`Otl1er(n- 9)
`
`Figure 1 Subject disposition. Full analysis set {FAS) : all randomised subjects who received 2 1 dose of study drug and
`had 3 1 efficacy assessment. Safety population : all randomised subjects who received 2 1 dose of double-blind study
`medication and/or took tolterodine ER in the run-in period. Sample size was determined from a subset of data from two
`of the fesoterodine Phase 3 studies that included subjects previously on tolterodine ER 4 mg with a change in UUI from
`baseline week 0 to week 2 S 50% (non-responders) and a week 0 UUI value 3 2. Sample size was calculated using a two-
`sample I test to compare fesoterodinc 8 mg and placebo (0.05 2-sided significance level). A sample size of 226 in each arm
`would have > 90% power to detect a difference in mean change from baseline in UUI episodes of -0.98 if the common
`standard deviation was 3.0, as observed previously. The within-group mean change from baseline to week 12 for
`fesoterodine 8 mg arm was expected to be no less than that of 8 mg vs. placebo, and thus this sample size had 3 90%
`power to detect a difference in frequency of UUI episodes.
`
`© 2014 The Authors International Journal of Clinical Practice Published by John Wiley 8: Sons Ltd
`Int} Clin Pract, September 2014, 68, 9, 1065-1073
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2090 - 0003
`
`

`
`1068
`
`Fesoterodine efficacy after suboptimal tolterodine response
`
`Table 1 Baseline demographical and clinical characteristics
`
`Placebo (n = 301)
`
`Fesoterodine (n = 308)
`
`Sex, n ("/o)
`Male
`Female
`
`Mean (SD) age, y
`Race. n ('11:)
`White
`Black
`Asian
`Other
`
`Mean weight, kg (range)
`Mean (SD) body-mass index, kglmz
`Mean duration since DAB diagnosis, y (range)
`Median duration since diagnosis, 51*
`DAB symptoms at baseline, mean (SD)*
`UUI episode5l24 h
`Micturitionsl24 h
`
`Urgency episodes.'24 h
`
`57 (19)
`244 (81)
`58.2 (13.2)
`
`246 (81.7)
`37 (12.3)
`8 (2.7)
`10 (3.3)
`81.5 (458-1560)
`30.0 (5.9)
`6.6 (0.5—50.1)
`4.6
`
`3.83 (2.5)
`12.48 (3.8)
`11.26 (4.0)
`
`55 (18)
`253 (82)
`57.3 (13.4)
`
`251 (81.5)
`38 (12.3)
`8 (2.6)
`11 (3.6)
`81.3 (450-1941)
`29.8 (5.7)
`7.0 (0.5—46.5)
`4.7
`
`3.93 (2.5)
`12.44 (3.6)
`11.38 (4.0)
`
`Data for subjects who were randomised and received doub|e—b|ind treatment, except where noted. *Data for randomised subjects
`(placebo, n = 320; fesoterodine, n = 322). *Data for the full analysis set of subjects with symptom and change from baseline to week
`12 (LOCF) data (placebo, n = 279; fesoterodine, n = 292). OAB, overactive bladder.
`
`placebo (p = 0.0079; Figure 2). The reduction in
`UUI episodes from baseline to week 4 was also sig-
`nificantly greater with
`fesoterodine
`vs.
`placebo
`(p : 0.0031; Figure 2).
`The mean reduction from baseline in urgency epi-
`sodes.’24 h was significantly greater with fesoterodine
`8 mg vs. placebo at week 12 (p : 0.0438), but not at
`week 4 (p : 0.2172; Figure 2). The mean reduction
`from baseline in micturitions/24 h was significantly
`greater with fesoterodine vs. placebo at week 4
`(p = 0.0463), and the difference was not statistically
`significant at week 12 (p = 0.0931; Figure 2). The
`diary-dry rate was significantly higher in the fesoter-
`odine group vs.
`the placebo group at week 4
`(p = 0.0427), but not at week 12 (p = 0.1461; Fig-
`ure 2).
`a > 50%
`subjects with
`of
`percentages
`The
`(p : 0.0027) or > 70% (p : 0.0010)
`reduction in
`UUI episodes from baseline (after the tolterodine ER
`run-in) to week 12 were significantly higher in the
`fesoterodine group vs. the placebo group (Figure 2).
`At week 4, 50% (p : 0.0537) and 70% (p : 0.1648)
`responder rates were not different between the treat-
`ment groups
`(Figure 2). Similarly, percentages of
`subjects with a > 50% (60% vs. 73%. p = 0.0023) or
`> 70% (47% vs. 61%, p : 0.0020) reduction in UUI
`episodes from eligibility (before the tolterodine ER
`run-in) to week 12 were significantly higher in the
`fesoterodine group vs.
`the placebo group, but 50%
`(54% vs. 63%, p : 0.089) and 70% (40% vs. 46%,
`
`p = 0.2229) responder rates from eligibility to week
`4 were not significantly different.
`PPBC
`in
`Categorical
`changes
`from baseline
`(p < 0.0001) and UPS (p : 0.0095) scores at week
`12 were significantly better in the fesoterodine 8 mg
`group vs.
`the placebo group (Figure 3). Changes
`from baseline
`in
`OAB-q
`Symptom Bother
`(p : 0.0001) and total HRQL (p < 0.0001) scores, as
`well
`as
`in
`the Concern
`(p < 0.0001), Coping
`(p < 0.0001), Sleep (p = 0.0012) and Social Interac-
`tion (P= 0.0123) domains. were also significantly
`better for fesoterodine vs. placebo at week 12 (Fig-
`ure 3).
`Dry mouth and constipation were the only treat-
`ment-emergent adverse event
`(AE5) occurring in
`2 2% of subjects in any treatment arm; most cases
`were moderate to moderate in severity (Table 2).
`Urinary retention was reported by two subjects dur-
`ing the tolterodine run-in phase; neither case was
`considered severe. Two deaths were reported during
`the study. A 72-year-old woman who was a screen
`failure and did not take any study medication died
`of respiratory failure with urosepsis. A 73-year-old
`woman in the placebo group discontinued treatment
`after being diagnosed with gastric cancer and subse-
`quently died because of disease progression 104 days
`after starting the study. Serious treatment—emergent
`AEs and discontinuations because of
`treatment-
`
`related AEs were generally similar with all treatments
`(Table 2).
`
`© 2014 The Authors International Journal of Clinical Practice Published by John Wiley & Sons Ltd
`Int J Cfin Pratt, September 2014, 68, 9, 1065-1073
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2090 - 0004
`
`

`
`Fesoterodine efficacy after suboptimal tolterodine response
`
`1069
`
`(A)
`
`UUI episodesl24 h
`Week 4
`Week 12
`
`(B)
`
`Diary-dry rate
`
`changefrombaseline 1'
`L5mean
`
`in =
`
`265
`
`279
`
`279
`
`292
`
`(C)
`
`Micturitionsl24 h
`Week 4
`Week 12
`
`changefrombaseline
`L5mean
`
`Subjects,%
`frombaseline
`
`Urgency episodesl24 h
`Week 4
`Week 12
`
`(D)
`
`
`
`LSmeanchange
`
`n =
`
`266
`
`279
`
`279
`
`292
`
`=
`
`265
`
`279
`
`279
`
`292
`
`(E)
`
`50% UUI response rate
`
`(F)
`
`70% UUI response rate
`
`Subjects,%
`
`Subjects,%
`
`Week 4
`265
`279
`
`n =
`
`Week 12
`279
`292
`
`I:I Placebo
`
`- Fesoterodine
`
`Figure 2 Changes from baseline to weeks 4 and 12 in diary variables. (A) UUI episodes;'24 h; (B) diary-dry rate; (C)
`micturitions/24 h; (D) urgency episodes."24 h; (E) 50% responder rates; (F) 70% responder rates. *p < 0.05; lip < 0.01.
`
`Discussion
`
`Fesoterodine 8 mg treatment was effective and well
`tolerated in subjects who had a suboptimal response
`to tolterodine ER 4 mg. The data support
`the
`hypothesis that significant UUI
`reduction can be
`achieved with fesoterodine 8 mg in patients who
`respond suboptirnally to tolterodine ER 4 mg, as
`approximately 70% of fesoterodine-treated subjects
`had a reduction in UUI episodes of 50% or greater
`
`from the eligibility (203/279) or baseline (204/292)
`visits to week 12 and approximately 60% had a
`reduction in 70% or greater
`(eligibility, 170/279;
`baseline, 172/292). Further, post hoc analysis revealed
`a significant
`reduction in UUI episocles.’24 h (LS
`mean :l:SE) from eligibility to week 12 for fesotero-
`dine-
`(—2.S4 i 0.17, n : 279) vs. placebo-treated
`(—2.40 i 0.17,
`in : 275)
`subjects
`(p : 0.0252).
`Patient-reported outcomes measuring bladder-related
`problems, urgency,
`symptom bother, and HRQL
`
`© 2014 The Authors International Journal of Clinical Practice Published by John Wiley 8: Sons Ltd
`Int} Ciin Pract, September 2014, 68, 9, 1065-1073
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2090 - 0005
`
`

`
`1070
`
`Fesoterodine efficacy after suboptimal tolterodine response
`
`(A)
`
`PPBC
`
`100
`
`30
`
`% 50
`3U
`
`£4
`9?,
`
`40
`
`20
`
`Placebo
`267
`
`n =
`
`Fesoterodine
`291
`
`(C) OAB-q symptom bother
`0
`
`-18.11i1.72
`
`53
`+1tn
`‘*2II‘)
`7'
`
`L. C:
`
`
`
`
`
`LSmeanchangefrombaseline 4.C)
`
` - 2 2-Point
`14.4611.59
`LSmeanchangefrombaseline 3
`
`
`
`(B)
`
`100
`
`UPS
`
`80
`
`50
`
`Subjects,% 40
`
`20
`
`El Improvement
`
`El No change
`
`- Deterioration
`
`Placebo
`267
`
`n =
`
`Fesoterodine
`291
`
`OAB-q HRQL and domains
`
`I: Placebo
`- Fesoterodine
`
`1'
`
`
`
`
`
`
`24.11i1.75
`
`23.73i1.74
`
`22.07$1.77
`
`21.5521:1.55
`
`
`15.98i1.77
`
`15.55:1.80
`
`15.'I0i1.73
`142711.44
`
`
`10.14i1.47
`
`
`
`
`
`
`
`
`
`
`im provement
`
`2 1-Point
`improvement
`
`2 No change
`
`- Deterloratlon
`
`
`
`30
`
`is.»D
`
`286
`
`Figure 3 Patient—reported outcomes at week 12. (A) PPBC; (B) UPS; (C) OAB-q. *p < 0.05; lp < 0.01; 3p < 0.001.
`
`were significantly improved in these subjects, sug-
`gesting that
`the improvements with fesoterodine
`8 mg were clinically meaningful.
`The present results are consistent with two head-
`to-head prospective studies comparing fesoterodine
`8 mg with tolterodine ER 4 mg (8,9). Significantly
`greater improvements with fesoterodine 8 mg vs. tol-
`terodine ER 4- mg were observed for UUI episodes
`and other diary variables and patient-reported out-
`comes, as well as significantly higher diary-dry rates
`(8,9). However, the incidence of dry mouth for feso-
`terodine—treated subjects (28%) (8,9) was higher than
`in the present study (16.6%).These data are also con-
`sistent with an open-label,
`flexible-dose study of
`
`fesoterodine in subjects with OAB who reported dis-
`satisfaction with tolterodine treatment (ER or imme-
`diate-release) within
`the
`previous
`2 years
`(5).
`Significant improvements from baseline to week 12
`were observed in UUI episodes, micturitions, urgency
`episodes, and scores on the PPBC and OAB-q with
`fesoterodine. Approximately, 80% of subjects who
`were dissatisfied with previous tolterodine treatment
`reported being ‘satisfied’ or ‘very satisfied’ with flexi-
`ble-dose fesoterodine treatment.
`
`Studies with other antimuscarinic agents have also
`shown that subjects with DAB may be successfully
`treated with one antimuscarinic after unsuccessful
`
`treatment with another (6,7). These results, together
`
`© 2014 The Authors International Journal of Clinical Practice Published by John Wiley 8r Sons Ltd
`Int} Cfin Pratt, September 2014, 68, 9, 1065-1073
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2090 - 0006
`
`

`
`Table 2 Treatment-emergent adverse events*
`
`Fesoterodine efficacy after suboptimal tolterodine response
`
`1071
`
`Number of subjects We)
`
`Tolterodine ER (:1 = 990)
`
`Placebo (n = 301)
`
`Fesoterocline (n = 308)
`
`Open-label
`
`Double-blind
`
`Subjects with AEs
`All-causality
`Treatment-related
`Discontinued because of AEs
`
`All-causality
`Treatment-related
`Subjects with serious AEs
`AE rates)
`
`Dry mouth)
`Constipationi
`
`134 (13.5)
`84 (8.5)
`
`12 (1.2)
`7 (0.7)
`3 (0.3)
`
`61 (6.2)
`11 (1.1)
`
`75(24.9)
`30 (10.0)
`
`12 (4.0)
`6 (2.0)
`7 (2.3)
`
`12 (4.0)
`4 (1.3)
`
`110 (35.1)
`68 (22.1)
`
`11 (3.5)
`7 (2.3)
`5 (1.6)
`
`51 (16.6)
`12 (3.9)
`
`
`
`*|nc|udes data up to 7 days aiter last dose of study drug. (AEs occurring in 2 2% of subjects in any treatment group.
`
`that
`from the present study, suggest
`with results
`switching medication is a valid approach for patients
`who fail
`to achieve OAB symptom resolution with
`antimuscarinic pharmacotherapy.
`As noted above, several studies provide evidence
`that
`the highest
`approved dose of
`fesoterodine
`(8 mg) is significantly more effective than the highest
`approved dose of tolterodine ER (4 mg, which is the
`only approved dose of tolterodine ER for most OAB
`populations) (8-10). In addition, the results of a post
`hoc analysis demonstrate that
`fesoterodine 8 mg is
`significantly more effective in improving UUI epi-
`sodes and other diary variables than fesoterodine
`4 mg (19). This is
`important, as a dose-response
`effect for UUI has not been demonstrated for most
`
`antimuscarinic agents with multiple approved doses
`(20,21).
`Many patients stop taking their OAB medication
`because
`the drug ‘didn’t work as
`expected’ or
`because of side effects (22). The availability of flexi-
`ble dosing with newer antimuscarinic medications
`affords additional
`treatment options when current
`antimuscarinic
`treatment
`fails. because
`clinicians
`
`can adjust patients’ dosage in an attempt to achieve
`favourable efficacy and tolerability before consider-
`ing more invasive treatment options (4). Data for
`three flexible-dose fesoterodine studies,
`in which
`
`subjects were initiated on the 4-mg dose and had
`the opportunity to escalate to the 8—mg dose based
`on efficacy and tolerability, have been analysed after
`stratification by subjects’ dose escalation status (23-
`25). In each study, subjects who escalated had more
`severe symptoms at baseline and a smaller reduc-
`tion in diary Variables and fewer AEs before the
`dose escalation choice point (23-25). By the end of
`each study, efficacy and tolerability outcomes were
`
`similar among subjects who escalated and those
`who did not
`(23-25). These findings underscore
`the importance of having an alternative antimuscar—
`inic option or dose escalation when there is a sub-
`optimal
`response
`to
`the
`first
`antimuscarinic
`medication.
`
`Strengths of this study include that it was a pro-
`spectively designed, randomised. double-blind, pla-
`cebo-controlled trial
`to assess
`the efficacy and
`tolerability of fesoterodine 8 mg in a population
`with a predefined suboptimal response to toltero-
`dine ER 4 mg.
`In contrast
`to previous ‘switching’
`studies,
`this study was unique in identifying a sub-
`optimal response by analysing UUI data before ran-
`domisation.
`In addition,
`the evaluation of efficacy
`at
`early time points
`and the incorporation of
`patient-reported outcomes provided measures of the
`onset and achievement of OAB symptom relief,
`which are important to patients and critical factors
`in their decision on whether to continue treatment.
`
`The use of a 2-week run-in period and a threshold
`of a S 50% reduction in UUI episodes to identify
`suboptimal
`responders to tolterodine ER are sup-
`ported by previous evidence (11,l7,18). Tolterodine
`ER was not
`included as
`an active comparator
`because the greater efficacy of fesoterodine 8 mg vs.
`tolterodine ER 4 mg has been demonstrated previ-
`ously (8,9).
`This study was limited by the measurement of
`tolterodine treatment response based only on UUI
`episodes/24 h; other symptoms may also have dem-
`onstrated a suboptimal response to treatment with
`tolterodine ER 4 mg.
`It
`is possible that
`a
`longer
`run-in
`period may
`have
`captured
`additional
`responders to tolterodine ER 4 mg, although the
`majority of response is known to occur within the
`
`© 2014 The Authors International Journal of Clinical Practice Published by John Wiley 8: Sons Ltd
`Int} Cfin Pract, September 2014, 68, 9, 1065-1073
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2090 - 0007
`
`

`
`1072
`
`Fesoterodine efficacy after suboptimal tolterodine response
`
`In a 12-week, prospec-
`first 2 weeks of treatment.
`tive, open-label study of tolterodine ER 4 mg in
`1138 adult
`subjects with OAB who were either
`OAB treatment naive or had previously received
`OAB treatment other than tolterodine,
`the median
`
`percentage change from baseline in UUI episodes
`was assessed at weeks 1. 4 and 12 (26). After week
`1 of tolterodine ER 4 mg treatment, 72% of the
`maximum reduction in UUI episodes was demon-
`strated in both treatment-naive and previously trea-
`ted patients.
`In a subsequent post hm: analysis of
`the data from this study,
`the onset of treatment
`efficacy was assessed based on changes in UUI epi-
`sodes for treatment days 5, 6 and 7 (27). For sub-
`jects with 2 1 UUI episodes at baseline, the median
`percentage decrease from baseline in UUI episodes
`was 50% at day 5, 67% at day 6, and 75% at day
`7 of tolterodine ER treatment
`(all p <0.0001 vs.
`baseline). Using a 50% reduction in UUI episodes
`to define responders,
`the responder rate was 58%
`on day 5, 69% on day 6, and 71% on day 7 of tol-
`terodine ER treatment. These results indicating that
`subjects with OAB experience significant
`improve-
`ments in UUI episodes and high responder rates,
`based on a 50% reduction threshold, as early as
`week 1 of treatment with tolterodine ER 4 mg sup-
`ported the 2-week duration of the open-label run-
`in period in the present study. On balance, the 2-
`week run-in period allowed a pragmatic approach
`to patient enrolment while maintaining a meaning-
`ful period for assessment.
`
`Conclusions
`
`Subjects with OAB who responded suboptimally to
`tolterodine ER 4 mg achieved significant
`improve-
`ments in UUI episodes after 12 weeks of treatment
`with fesoterodine
`3 mg vs.
`placebo. Significant
`improvements in the number of urgency episodes,
`UUI responder rates, and scores on the PPBC, UPS
`and all OAB-q scales and domains at week 12 also
`were observed with fesoterodine vs. placebo treat-
`ment. Fesoterodine 8 mg was well tolerated in sub-
`optimal responders to tolterodine ER.
`
`Acknowledgments
`
`Funding for this study was provided by Pfizer Inc,
`and Pfizer
`employees participated in the study
`design, collection and analysis of data and manu-
`script preparation. Medical writing assistance was
`provided by Diane DeHaven-Hudkins, PhD and
`Colin Mitchell, PhD of Complete Healthcare Com-
`munications, Inc., and was funded by Pfizer Inc. We
`thank the investigators and patients who participated
`in this study.
`
`Author contributions
`
`All authors participated in the concept/design, data
`interpretation, drafting and critically revising the
`article and approval of submission. Statistical analysis
`was conducted by MC.
`
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